Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) that constitutes the leading cause of neurologic disability in young adults. Astrocytes play an important role in MS, but the pathways controlling astrocyte activity in MS are poorly characterized. The study of these pathways is likely to identify mechanisms of disease pathogenesis and potential therapeutic targets for MS. We found that type I interferon receptor 1 (IFNAR1) signaling up-regulates the expression of the ligand- activated transcription factor aryl hydrocarbon receptor (AhR) in astrocytes and limits disease development in the EAE (experimental autoimmune encephalomyelitis) model of MS. Indeed, nasal administration of interferon-E (IFN-E which enters the CNS when administered nasally) suppresses acute EAE by a mechanism mediated by IFNAR1 and AhR in astrocytes. We found that AhR agonists derived from dietary tryptophan limit EAE development via AhR in astrocytes and these agonists are decreased in MS patients, suggesting that deficient AhR activation contributes to MS pathogenesis. Our data generated using acute disease models identify IFNAR1/AhR signaling as a novel pathway that integrates endogenous and environmental signals to control astrocyte functions relevant to MS pathology. Astrocytes, however, also play important roles in chronic CNS inflammation and in the progressive phase of MS for which limited therapeutic approaches are available. Thus, I hypothesize that IFN-I/AhR signaling in astrocytes limits chronic CNS inflammation and is a potential therapeutic target in progressive MS: SPECIFIC AIM 1. WHAT IS THE ROLE OF IFNAR1/AHR SIGNALING IN ASTROCYTES DURING PROGRESSIVE EAE? Astrocytes play a central role in MS pathogenesis, particularly in the progressive phase of MS for which limited therapeutic options are available. I propose to 1) Determine the role of IFNAR1/AhR signaling in astrocytes in a progressive EAE model that recapitulates unique aspects of human progressive MS, and 2) Define the mechanisms by which IFNAR1/AhR signaling in astrocytes limits the development of progressive EAE. SPECIFIC AIM 2. CAN AHR SIGNALING IN THE CNS BE TARGETED TO TREAT MS? Based on its anti-inflammatory effects, AHR activation in the CNS with nasally administered agonists may represent a new MS therapy. I propose to: 1) Define the effects of intranasal administration of the non-toxic AhR agonist ITE on astrocytes and CNS inflammation, and 2) Evaluate the therapeutic effects of intranasal ITE administration in a mouse EAE model that recapitulates important aspects of progressive MS. SPECIFIC AIM 3. HOW ARE ASTROCYTE SUBPOPULATIONS DEFINED IN EAE? In addition to IFNAR1/AhR signaling, other pathways are likely to limit astrocyte pathogenic activities in EAE and MS. I propose to: 1) Identify novel astrocyte populations relevant for development of acute EAE using single-cell RNA sequencing, and 2) Analyze these astrocyte subpopulations in a model of progressive EAE.